US007544192B2

(12) United States Patent (10) Patent No.: US 7,544,192 B2 Eaton et al. (45) Date of Patent: Jun. 9, 2009

(54) SINUS DELIVERY OF SUSTAINED RELEASE 5,443,498 A 8, 1995 Fontaine THERAPEUTICS 5,512,055 A 4/1996 Domb et al. 5,664,567 A 9, 1997 Linder (75) Inventors: Donald J. Eaton, Woodside, CA (US); 5,693,065. A 12/1997 Rains, III Mary L. Moran, Woodside, CA (US); 5,792,100 A 8/1998 Shantha Rodney Brenneman, San Juan Capistrano, CA (US) (73) Assignee: Sinexus, Inc., Palo Alto, CA (US) (Continued) (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 U.S.C. 154(b) by 992 days. WO WOO1/02024 1, 2001 (21) Appl. No.: 10/800,162 (22) Filed: Mar 12, 2004 (Continued) (65) Prior Publication Data OTHER PUBLICATIONS US 2005/OO437O6A1 Feb. 24, 2005 Hosemann, W. et al. (Mar. 2003, e-pub. Oct. 10, 2002). “Innovative s Frontal Sinus Stent Acting as a Local Drug-Releasing System.' Eur: Related U.S. Application Data Arch. Otorhinolarynolo. 260:131-134. (60) Provisional application No. 60/454,918, filed on Mar. (Continued) 14, 2003. Primary Examiner Kevin C Sirmons (51) Int. Cl Assistant Examiner Catherine NWitczak A. iM sI/00 (2006.01) (74) Attorney, Agent, or Firm Morrison & Foerster LLP (52) U.S. Cl...... 604/506; 604/510; 604/514 (57) ABSTRACT (58) Field of Classification Search ...... 604/93.01, 604/891.1. 890.1, 57, 59-64, 510, 514,506; S lication file f 606/196 The invention provides biodegradable implants for treating ee application file for complete search history. sinusitis. The biodegradable implants have a size, shape, den (56) References Cited sity, Viscosity, and/or mucoadhesiveness that prevents them from being Substantially cleared by the mucociliary lining of U.S. PATENT DOCUMENTS the sinuses during the intended treatment period. The biode 4,580,568 A 4, 1986 Gianturco gradable implants include a Sustained release therapeutic, 4,753,636 A 6, 1988 Free e.g., an antibiotic, a steroidal anti-inflammatory agent, or 5,035,706 A 7, 1991 Giantureo et al. both. The biodegradable implants may take various forms, 5,116,311 A 5, 1992 Lofstedt Such as rods, pellets, beads, strips, or microparticles, and may 5,139,832 A 8/1992 Hayashi et al. be delivered into a sinus in various pharmaceutically accept 5,189,110 A 2f1993 Ikematu et al. able carriers. 5,246,455 A 9, 1993 Shikani 5,342.296 A 8, 1994 Persson et al. 15 Claims, 2 Drawing Sheets

US 7,544,192 B2 Page 2

U.S. PATENT DOCUMENTS 2008.0113000 A1 5/2008 Hunter et al. 2008/01 19693 A1 5/2008 Makower et al. 5,928, 190 A 7, 1999 Davis 2008.0125626 A1 5/2008 Chang et al. 6,054,122 A 4, 2000 MacPhee et al. 2008. O132938 A1 6/2008 Chang et al. 6,149,944 A 11, 2000 Jeong et al. 2008. O145514 A1 6/2008 Hunter et al. 6,297.227 B1 10, 2001 Johnson 2008. O154237 A1 6/2008 Chang et al. 6,543,452 B1 4, 2003 Lavigne 2008. O154250 A1 6/2008 Makower et al. 6,555,566 B2 4, 2003 Ponikau 2008. O195041 A1 8, 2008 Goldfarb et al. 6,565,597 B1 5/2003 Fearnot et al. 2008/0228O85 A1 9, 2008 Jenkins et al. 6,749,617 B1 6, 2004 Palasis et al. 2008/0234720 A1 9/2008 Chang et al. 6,884,260 B2 4, 2005 Kugler et al. 2008/0243140 A1 10/2008 Gopferich et al. 6,945,992 B2 9, 2005 Goodson, IV et al. 6,966,923 B2 11/2005 Gittings FOREIGN PATENT DOCUMENTS RE39,321 E 10, 2006 MacPhee et al. 7,361,168 B2 4, 2008 Makower et al. WO WO-2004/082525 A2 9, 2004 2002fOO51793 A1 5, 2002 Drabick WO WO-2004/082525 A3 9, 2004 2002/011 1603 A1 8, 2002 Cheikh ...... 604/8911 WO WO-2006/02O180 A2 2, 2006 2003/O133877 A1 T/2003 Levin WO WO-2006/02O180 A3 2, 2006 2004.0043052 A1 3, 2004 Hunter et al. WO WO-2006/107.957 A2 10, 2006 2004/O116958 A1 6, 2004 Gopferich et al. WO WO-2006/107.957 A3 10, 2006 2005/02O3605 A1 9, 2005 Dolan WO WO-2007 134215 A2 11/2007 2005/024O147 A1 10, 2005 Makower et al. WO WO-2007 134215 A3 11, 2007 2005.0245906 A1 11/2005 Makower et al. OTHER PUBLICATIONS 2006,0004286 A1 1, 2006 Chang et al. 2006, OOO4323 A1 1, 2006 Chang et al. Roumestan, C. et al. (2003). “Fluticasone Propionate and 2006, OO63973 A1 3, 2006 Makower et al. Mometasone Furoate Have Equivalent Transcriptional Potencies.” 2006/0095066 A1 5, 2006 Chang et al. Clinical and Experimental Allergy 33: 895-901. 2006/0106361 A1 5, 2006 Muni et al. Shikani, A.H. (Aug. 1996). “Use of Antibiotics for Expansion of the 2006/0162722 A1 T/2006 Boehm et al...... 128.200.14 Merocel(R) Packing Following Endoscopic Sinus Surgery.” ENTJour 2006/0210605 A1 9, 2006 Chang et al. nal 75(8):524-528. 2006/0265042 A1 11, 2006 Catanese, III et al. Thierry, B. et al. (Nov./Dec. 2003). “Bioactive Coatings of 2006/0276871 A1 12, 2006 Lamson et al. Endovascular Stents Based on Polyelectrolyte Multilayers.” 2007,0005094 A1 1/2007 Eaton et al. Biomacromolecules 4:1564-1571. 2007/0129751 Al 6, 2007 Muni et al. Lavigne, F. et al. (2002). "Intrasinus Administration of Topical 2007/O131525 A1 6, 2007 Lu et al. Budesonide to Allergic Patients With Chronic Rhinosinusitis Follow 2007/0135789 A1 6, 2007 Chang et al. ing Surgery.” The Laryngoscope 1 12, seven pages. 2007/0167682 A1 7/2007 Goldfarb et al. Min, Y-G. et al. (1995). "Application of Polylactic Acid Polymer in 2007,019 1922 A1 8, 2007 Hartley the Treatment of Acute Maxillary Sinusitis in Rabbits.” Acta 2007/02O8252 A1 9, 2007 Makower Otolaryngol. 115:548-552. 2007/0208301 A1 9, 2007 Evard et al. Min, Y-G. etal. (1995). “Mucociliary Activity and Histopathology of 2007/0269385 A1 11/2007 Yun et al. Sinus Mucosa in Experimental Maxillary Sinusitis: A Comparison of 2007/O293727 A1 12, 2007 Goldfarb et al. Systemic Administration of Antibiotic and Antibiotic Delivery by 2007/0293946 A1 12, 2007 Gonzales et al. Polylactic Acid Polymer.” Laryngoscope 105:835-842. 2008, OO15540 A1 1, 2008 Muni et al. Piskunov, S. et al. (1993). “The Prolongation of Drug Action in the 2008.OO58295 A1 3, 2008 Chaudry Treatment of Diseases of the Nose and Paranasal Sinuses.” Rhinology 2008.OO58296 A1 3, 2008 Chaudry 31:33-36. 2008.0089952 A1 4, 2008 Hunter et al. International Search Report mailed Feb. 24, 2006 for PCT Applica 2008.OO971.54 A1 4, 2008 Makower et al. tion No. PCT/US04/07828 filed Mar. 12, 2004, 2 pages. 2008.OO97239 A1 4, 2008 Chang et al. Lapchenko, A.S. et al. (Jun. 1996). “Polyphosphazene Prosthesis of 2008.OO97295 A1 4, 2008 Makower et al. the Frontonasal Bypass in Surgical Treatment of Acute and Chronic 2008.OO97400 A1 4, 2008 Chang et al. Inflammation of the Frontal Sinuses.” Vestnik Otorinolarinologii, 2008.OO97514 A1 4, 2008 Chang et al. tWO pages. 2008.OO975.15 A1 4, 2008 Chang et al. Piskunov, S.Z. et al. (1989). "Application of Drugs Based on Poly 2008.OO97516 A1 4, 2008 Chang et al. mers in the Treatment of Acute and Chronic Maxillary Sinusitis.” 2008.OO97581 A1 4, 2008 Shanley Vestnik Otorinolaringologii (3)33-35. 2008. O103361 A1 5/2008 Makower et al. 2008/O103521 A1 5/2008 Makower et al. * cited by examiner U.S. Patent Jun. 9, 2009 Sheet 1 of 2 US 7,544.192 B2

Fléauee A

AéuKE t8 U.S. Patent Jun. 9, 2009 Sheet 2 of 2 US 7,544,192 B2

Aétage 2A

Aataee 2.É. US 7,544,192 B2 1. 2 SINUS DELIVERY OF SUSTAINED RELEASE agent dispersed within a biodegradable matrix, and which has THERAPEUTICS at least one characteristic that Substantially prevents clear ance of the implant from the sinus by its mucociliary layer RELATED APPLICATIONS during the intended treatment period after delivery of the implant into the sinus. Characteristics such as size, shape, This application claims priority from U.S. Application Ser. density, Viscosity, mucoadhesiveness, or a combination No. 60/454,918, filed Mar. 14, 2003. thereof may be altered to substantially prevent this clearance. The biodegradable implant may include various therapeu FIELD OF THE INVENTION tic agents, including, but not limited to, anti-infective agents, 10 anti-inflammatory agents, and combinations thereof. This invention relates to biodegradable implants and meth Examples of anti-infective agents include antibacterial ods for placing one or more of these implants into a paranasal agents, antifungal agents, antiviral agents, and antiseptics. sinus. The implants provide local Sustained release of a thera The anti-inflammatory agent may be a nonsteroidal anti-in peutic agent for the prophylaxis or treatment of sinusitis. flammatory agent or a steroidal anti-inflammatory agent. In a Included in the description are implants delivered in such 15 preferred variation, steroidal anti-inflammatory agents are various forms as pellets, rods, strips, and microparticles. used. BACKGROUND OF THE INVENTION The matrix of the implant may be made from any biode gradable and biocompatible polymer, including such poly The paranasal sinuses are air-filled cavities within the mers as mucoadhesive polymers, poly(ortho esters), and poly facial skeleton. Each paranasal sinus is contiguous with a (lactic-co-glycolic)acid (PLGA) copolymer. The nasal cavity and drains into the nose through a sinus ostium. biodegradable polymer matrix may also be formed as a rod, Although other factors may be involved, the development of pellet, bead, strip, or microparticle, and placed in a pharma sinusitis (inflammation of the mucosal lining of the sinuses) is ceutically acceptable carrier if desired. When the biodegrad most often attributed to blockage of one or more of these sinus able implant is a microparticle, usually a plurality of micro ostia, followed by mucostasis and microbial overgrowth in 25 particles are delivered into the sinus to treat sinusitis. The the sinus cavity. Ostial blockage may stem from predisposing microparticles may or may not be porous, and may have an anatomical factors, or inflammation and edema of the mucous average diameter of between about 0.1-500 um, between lining in the area of the ostia, arising from Such etiologies as about 0.1-100 um, between about 0.1-50 um, or between viral or bacterial upper respiratory infection or chronic aller about 0.1-10 um. In some instances, the form of the biode gic processes. 30 gradable implant may change after delivery into the sinus. For Traditionally, sinusitis has been medically managed by the example, a poly(ortho ester) implant in the form of a strip oral administration of antibiotics and steroids. However, pen having a series of predetermined fracture lines or Zones may etration of these systemically delivered agents into the sinus fracture into a plurality of Smaller segments as it degrades mucosa is limited due to poor blood flow to the sinuses. along the fracture lines in the sinus. Therapeutic agents contained in aqueous solutions, creams, 35 The biodegradable implant may deliver a sustained release or gels, for topical application in the nose have also been therapeutic agent over at least about one week, over at least formulated, but usually never travel far enough into the nose about two weeks, over at least about three weeks, over at least to reach the sinuses, are blocked from entering the sinuses due about four weeks, over at least about six weeks, over at least to obstructed ostia, or have Such short contact with the sinus about two months, or over at least about three months. In a mucosa that absorption of the agent is low. For similar rea 40 preferred variation, the Sustained release therapeutic agent is Sons, nasally inhaled steroid and anti-infective aerosols that delivered into the sinus over about three weeks. have been developed to treat sinusitis are equally ineffective. The delivery of amplicillin from a poly(lactic-co-glycolic) The biodegradable implants may be delivered into a sinus acid (PLGA) film to increase residence time of the antibiotic using devices of various designs, but at least which include a in rabbit sinuses has been investigated for the treatment of 45 pusher and a conduit, e.g., a catheter, needle, orangiocatheter. sinusitis (Minet al. Mucociliary Activity and Histopathology For example, the pusher and/or conduit may be made such of Sinus Mucosa in Experimental Maxillary Sinusitis: A that they are variably stiffalong their lengths. In addition, the Comparison of Systemic Administration of Antibiotic and opening in the conduit through which the implant is delivered Antibiotic Delivery by Polylactic Acid Polymer. Laryngo may be positioned in the conduit side wall or at the tip. scope 105:835-342 (1995) and Minet al. Application of Poly 50 Furthermore, the distal portion of the conduit may be angu lactic Acid Polymer in the Treatment of Acute Maxillary lated to facilitate access of the sinus ostium if indicated. In Sinusitis in Rabbits. Acta Otolaryngol 115:548-552 (1995)). one variation, the distal portion is malleable such that the Although clinical signs of sinusitis improved, the procedure physician may angulate the conduit themselves just prior to for placing the film required that a hole be drilled through the accessing the sinus ostium. anterior wall of the maxillary sinus. 55 The biodegradable implants and devices for their deploy Consequently, a biodegradable implant for administering a ment may be used in a system for treating sinusitis. In general, Sustained release therapeutic agent to the paranasal sinuses the system works by first placing the conduit having one or for a prolonged time period without being Substantially more implants within its lumen either through a sinus ostium cleared by the mucociliary lining of the sinuses, and methods or a sinus wall. A pusher within the lumen of the conduit is for delivering the implant in a minimally invasive fashion 60 then distally advanced to slidably engage the implant(s) and may provide significant medical benefit for patients afflicted move it through an opening in the distal portion of the conduit with sinusitis. into the sinus. The opening may be in the conduit side wall or tip. Usually, the conduit will be preloaded with one or more SUMMARY OF THE INVENTION implants. In some instances, a tool for visualizing the sinus 65 ostium or sinus wall is desired. Examples of Such tools The present invention is a biodegradable implant for treat include endoscopes and computed tomography (CT) scan ing sinusitis that includes a Sustained release therapeutic S. US 7,544,192 B2 3 4 The biodegradable implants may also be used for reducing Therapeutic Agents inflammation from a sinus procedure. These implants would The therapeutic agents that may be used in the biodegrad also include a Sustained release therapeutic agent dispersed able implants include, but are not limited to, anti-infective within a biodegradable matrix and have at least one charac agents, anti-inflammatory agents, or a combination thereof. teristic that Substantially prevents clearance of the implants Anti-infective agents generally include antibacterial agents, from a sinus during a treatment period after delivery of the antifungal agents, antiviral agents, and antiseptics. Anti-in implant into the sinus. The treatment period may be of any flammatory agents generally include Steroidal and nonsteroi duration which the physician deems is suitable to reduce the dal anti-inflammatory agents. inflammation. Examples of antibacterial agents that may be incorporated 10 in the biodegradable implants include aminoglycosides, BRIEF DESCRIPTION OF THE DRAWINGS amphenicols, ansamycins, B-lactams, lincosamides, mac rolides, nitrofurans, quinolones, Sulfonamides, Sulfones, tet FIGS. 1A-1B are cross-sectional views of the distal portion racyclines, and any of their derivatives. In one variation, of an implant delivery device. In FIG. 1A, the biodegradable B-lactams are the preferred antibacterial agents. implant is delivered through a side opening in the conduit. In 15 B-lactams that may be included in the implants include FIG. 1B, the biodegradable implant is delivered through the carbacephems, carbapenems, cephalosporins, cephamycins, tip of the conduit. monobactams, oxacephems, penicillins, and any of their FIG. 2A is a cross-sectional view of a distal portion of a derivatives. In one variation, penicillins (and their corre multiple implant delivery device. sponding salts) are the preferred B-lactams. FIG. 2B is a cross-sectional view of a handle that may be The penicillins that may be used in the biodegradable coupled to the distal portion of the multiple implant delivery implants include amdinocillin, amdinocillin pivoxil, amox device shown in FIG. 2A. icillin, amplicillin, apalcillin, aspoxicillin, azidocillin, aZlocil lin, bacampicillin, benzylpenicillinic acid, benzylpenicillin DETAILED DESCRIPTION OF THE INVENTION Sodium, carbenicillin, carindacillin, clometocillin, cloxacil 25 lin, cyclacillin, dicloxacillin, epicillin, fenbenicillin, floxacil The biodegradable implants of this invention may take lin, hetacillin, lenampicillin, metampicillin, methicillin various forms, but are generally designed to have a size and Sodium, mezlocillin, nafcillin Sodium, oxacillin, penamecil shape appropriate for the intended method of delivery, e.g., lin, penethamate hydriodide, penicillin G benethamine, peni through the sinus ostium or by puncture through a sinus wall, cillin G benzathine, penicillin G benzhydrylamine, penicillin and a density, Viscosity, and/or mucoadhesiveness Such that 30 G calcium, penicillin Ghydrabamine, penicillin G potassium, the implant is not substantially cleared from the sinus over the penicillin G procaine, penicillinN, penicillin O, penicillin V. duration of treatment. Once within the sinus, the implant penicillin V benzathine, penicillin V hydrabamine, penime releases a therapeutic agent over a prolonged time period, for picycline, phenethicillin potassium, piperacillin, pivampicil example, over at least one week, over at least two weeks, over lin, propicillin, quinacillin, Sulbenicillin, Sultamicillin, at least three weeks, or over at least four weeks or more, to 35 talampicillin, temocillin, and ticarcillin. In one variation, treat sinusitis. amoxicillin may be included in the biodegradable implant. In another variation, the biodegradable implant includes ampi Definitions clin. Penicillins combined with clavulanic acid Such as Aug For purposes of this description, we use the following menting R (amoxicillin and clavulanic acid) may also be terms as defined in this section, unless the context of the word 40 used. indicates a different meaning. Examples of antifungal agents that may be used in the By 'sinus' it is meant all sinuses, i.e., the maxillary, eth biodegradable implants include allylamines, imidazoles, moid, frontal, and sphenoidal sinuses. polyenes, thiocarbamates, triazoles, and any of their deriva By “subject' it is meant mammalian subjects, preferably tives. In one variation, imidazoles are the preferred antifungal humans. Mammals include, but are not limited to, primates, 45 agents. farm animals, sport animals, cats, dogs, rabbits, mice, and Typically, if inclusion of an anti-inflammatory agent is ratS. desired, a steroidal anti-inflammatory agent, e.g., a corticos As used herein, the term “treat”, “treating, or “treatment” teroid, is employed. Examples of steroidal anti-inflammatory refers to the resolution, reduction, or prevention of sinusitis or agents that may be used in the implants include 21-acetox the sequelae of sinusitis. 50 ypregnenolone, alclometasone, algestone, amcinonide, As used herein, the term “therapeutic agent”, “active beclomethasone, betamethasone, budesonide, chloropred agent, and "drug” are used interchangeably and refer to any nisone, clobetasol, clobetaSone, clocortolone, cloprednol, Substance used to treat sinusitis. corticosterone, cortisone, cortivaZol, deflazacort, desonide, By “therapeutic amount it is meant a concentration of desoximetaSone, dexamethasone, diflorasone, diflucor therapeutic agent that has been locally delivered to a sinus 55 tolone, difluprednate, enoXolone, fluazacort, flucloronide, that is appropriate to safely treat sinusitis. flumethasone, flunisolide, fluocinolone acetonide, fluocino nide, fluocortin butyl, fluocortolone, fluorometholone, flu Biodegradable Implants perolone acetate, fluprednidene acetate, fluprednisolone, flu The implants of this invention generally include a thera randrenolide, fluticasone propionate, formocortal, peutic agent dispersed within a biodegradable polymer. The 60 halcinonide, halobetasol propionate, halometasone, halopre therapeutic agent may be homogeneously or inhomoge done acetate, hydrocortamate, hydrocortisone, loteprednol neously dispersed throughout the implant. Implant composi etabonate, maZipredone, medrysone, meprednisone, methyl tions may vary, depending, for example, on the particular prednisolone, mometasone furoate, paramethasone, predni therapeutic agent employed, duration of desired drug release, carbate, prednisolone, prednisolone 25-diethylamino-ac type of sinusitis being treated, and medical history of the 65 etate, prednisolone sodium phosphate, prednisone, prednival, patient. However, in all instances, the biodegradable implant prednylidene, rimexolone, tiXocortol, triamcinolone, triamci is formulated for Sustained release of the therapeutic agent. nolone acetonide, triamcinolone benetonide, triamcinolone US 7,544,192 B2 5 6 hexacetonide, and any of their derivatives. In one variation, sion of an antibacterial agent is desired in the PLGA matrix, budesonide is included in the implant as the steroidal anti alone or in combination with a steroidal anti-inflammatory inflammatory agent. In another variation, the steroidal anti agent, Augmentin R) may be used. If first-line antimicrobial inflammatory agent may be mometasone furoate. In yet therapy fails, or for penicillin allergy, a cephalosporin Such as another variation, the steroidal anti-inflammatory agent may ciprofloxacin or macrollide Such as erythromycin may be used be beclomethasone. in the PLGA matrix. The therapeutic agent may constitute from about 5% to The biodegradable implants may be solid or semisolid and about 90%, about 15% to about 75%, or about 30% to about take a variety of suitable forms, such as rods or approximately 60% by weight of the implant. The amount of therapeutic spherical or rectangular pellets, beads, Strips, or micropar agent used will usually depend on factors such as the particu 10 ticles, so long as their size and shape is compatible with the lar agent incorporated, the Suspected etiology of the sinusitis, selected sinus of implantation, and so long as the implants and the severity of clinical symptoms, but in all instances will exhibit the desired release kinetics and deliver an amount of usually be an amount that is therapeutic upon delivery into a drug therapeutic for the intended type of sinusitis. In one sinus. Ancillary agents such as topical decongestants may variation, the implant is a rod having a length of about 1 mm also be included. 15 to about 10 mm and a diameter of about 0.05 mm to about 5 mm. In another variation, the implant is a rod having a length Polymer Matrix of about 4 mm and a diameter of about 2 mm. In yet a further Selection of the biodegradable polymer matrix to be variation, the implant is a microparticle. When treating employed will vary depending on the residence time and sinusitis, a plurality of these microparticles with or without a release kinetics desired, method of implant delivery, particu carrier are delivered into the sinus. The microparticles may or lar therapeutic agent used, and the like. An exemplary list of may not be porous, and may have an average diameter of biodegradable polymers that may be used are described in between about 0.1-500 um, between about 0.1-100 um, Heller, Biodegradable Polymers in Controlled Drug Deliv between about 0.1-50 um, between about 0.1-10 um, between ery, In: “CRC Critical Reviews in Therapeutic Drug Carrier about 0.1-1 um, or between about 0.1-0.5 Lum. Systems”, Vol. 1. CRC Press, Boca Raton, Fla. (1987). In all 25 Also important is that the implant remain in the sinus instances, the polymer matrix when degraded results in physi during the intended period of drug delivery. The sinuses are ologically acceptable degradation products. The biodegrad lined with a ciliated epithelium and a layer of mucus. The cilia able polymer matrix may constitute at least about 10%, at beat continuously, causing the mucous layer to slowly flow least about 20%, at least about 30%, at least about 40%, at out of the sinus toward the pharynx. Accordingly, in order to least about 50%, at least about 60%, at least about 70%, at 30 effectively treat sinusitis with an implant, the implant must least about 80%, at least about 90%, or at least about 95% by typically remain in the sinus long enough to deliver a drug in weight of the implant. a therapeutic amount. The biodegradable implants of this In one variation, adhesiveness of the polymer matrix to the invention have a mucoadhesiveness, size, shape, Viscosity, sinus mucosa is particularly desired. Mucoadhesive polymers and/or density that allows a Substantial amount of the implant are typically hydrophilic, and upon moistening, Swell and 35 to remain in the sinus during the intended period of drug become adhesive. Examples of mucoadhesive polymers that delivery. may be employed in the biodegradable implants include Furthermore, the implant may be of a design that allows it homopolymers of acrylic acid monomers such as polyacrylic to take a form that is different after it is delivered into the sinus acid and any of its pharmaceutically acceptable salts; copoly from that before delivery. For instance, an implant delivered mers of acrylic acid and methacrylic acid, styrene, or vinyl 40 into the sinus as a rod or strip having a series of predetermined ethers; vinyl polymers such as polyhydroxyethyl acrylate, fracture lines or Zones may fracture into a plurality of smaller polyhydroxyethyl methacrylate, polyvinyl alcohol, and poly segments as it degrades along the fracture lines. vinyl pyrrolidone; cellulosic derivatives such as methyl cel lulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypro Additional Agents pyl cellulose, hydroxypropylmethyl cellulose, and The implants of this invention may further include compo carboxymethyl cellulose; polysaccharides such as alginic 45 nents such as preservatives, buffers, binders, disintegrants, acid, Sodium alginate, and tragacanth gum, collagen; gelatin: lubricants, and any other excipients necessary to maintain the and any combination thereof. structure and/or function of the implants. Furthermore, the In another variation, the biodegradable matrix is made implants may be placed in a pharmaceutically acceptable from an orthoester, alone or in combination with other mono 50 carrier, e.g., when the implants are microparticles, to form a mers. In a preferred variation, a poly(ortho ester) is used to Suspension Such as a semi-solid gel. Common gel bases constitute the polymer matrix. include, but are not limited to, carbomer, liquid paraffin, water, glycerol, propylene glycol, hyaluronic acid or sodium In yet a further variation, polymers of hydroxyaliphatic hyaluronate, or a combination thereof. The types of gels that carboxylic acids, either homo- or copolymers, are used to may be formed include, e.g., inorganic and organic gels, form the matrix. For example, polyesters including homo- or 55 hydrogels, or organogels. copolymers of D-lactic acid, L-lactic acid, racemic lactic In addition to microparticle density, the Viscosity of the gel acid, glycolic acid, caprolactone, and combinations thereof may be adjusted to a level that allows delivery into the sinus may be used. Copolymers of glycolic and lactic acid are of and prevents substantial clearance of the microparticles (im particular interest, where the rate of biodegradation is con plants) from the sinus. The gel may also be prepared in adhe trolled by the ratio of glycolic to lactic acid. The percent of 60 each monomer in poly(lactic-co-glycolic)acid (PLGA) sive form (using adhesive polymers such as polyacrylic acid, copolymer may be 0-100%, about 20-80%, about 30-70%, or Sodium carboxymethyl cellulose, or polyvinylpyrrolidone) to about 40-60%. In a preferred variation, a 50/50 PLGA increase the contact time of the therapeutic agent with the copolymer is used. sinus mucosa. In one variation, PLGA may be combined with budesonide 65 Release Kinetics to form the biodegradable sinus implant. In another variation, In general, the implants of this invention are formulated PLGA may be combined with mometasone furoate. If inclu with particles of a therapeutic agent dispersed within a bio US 7,544,192 B2 7 8 degradable polymer matrix, and formulated to provide Sus the opening will usually be approximately twice the diameter tained-release of the therapeutic agent. If made from a non of the implant. The pusher 24 is advanced distally within the swellable polymer, e.g., PLGA or poly(ortho ester), release of lumen 16 to slidably engage the implant 10 and move it up the the active agent from the matrix is probably achieved by ramp 26 through the side wall 14 into the sinus. In FIG. 1B, erosion of the biodegradable polymer matrix and by diffusion 5 the opening 20 is positioned at the tip 22 of the conduit 12, and of the particulate therapeutic agent into the mucous layer of pusher 24 is advanced distally within the lumen 16 to slidably the sinus. Factors that may influence the release kinetics engage the implant 10 and move it through the tip 22. include such characteristics as the size of the drug particles, Although the conduittips are shown to be blunt in the Figures, the solubility of the drug, the ratio of drug to polymer(s), the they may also be sharp and/or beveled, usually depending on method of implant manufacture, the implant Surface area 10 the implant delivery method. exposed, and the erosion rate of the matrix polymer(s). In the FIG. 2A shows a device that delivers multiple implants. case of polymer Swelling, as seen with hydrogels, a therapeu The device is similar to the single implant delivery device tic agent is released as liquid diffuses through exposed path having a conduit 28 with a side wall 30, a lumen 32, a distal ways in the implant. portion 34, an opening 36 in the distal portion 34, a tip 38, a The therapeutic agent may be released from the implant 15 pusher 40, and a ramp 42. Pusher 40 is distally advanced a over a prolonged time period including, but not limited to, at preset distance to slidably engage the most proximal implant least about one week, at least about two weeks, at least about 44 within lumen 32. The pusher 40 is then further distally three weeks, at least about four weeks, at least about 6 weeks, advanced a preset distance, e.g., a distance approximately at least about two months, or at least about three months. In equal to the length of one implant, to move the most distal one variation, the therapeutic agent is released over about two implant 46 through opening 36 into the sinus. weeks to about four weeks. A handle 48, as shown in FIG. 2B, may be coupled to conduit 28 such that the handle lumen forms a continuous Delivery Device lumen with the lumen32 of the conduit 28. The pusher 40 can The biodegradable implants may be placed into the sinus then slide through this continuous lumen. The handle 48 using various implant delivery devices. The device generally 25 further includes an injector 42, adjacent to and longitudinally includes a conduit, e.g., a catheter, having an elongate pusher aligned with the pusher 40, and a stepped slot 44 with various within its lumen. The conduit and pusher may be flexible or positions “O'”, “A”, “B”, and “C”. Initially, when the injector rigid, or may be designed to have varying degrees of stiffness 42 is pressed, the pusher 40 is distally advanced, and a key 46 along its length, e.g., the distal portion of the conduit may be coupled to the injector 42 moves the pusher 40 between stiffer than the proximal portion. In addition, the distal por 30 positions “O'” and 'A'. The distance between positions “O'” tion of the conduit may be variously angulated to facilitate and 'A' is approximately equal to the length of the dispensed positioning and advancement of the conduit through the sinus implant. Pusher 40 may then be rotated to move the key 46 ostium. For example, the distal portion may be angulated from position 'A' to position “B” in the stepped slot 44. from about 0° to about 175, from about 0° to about 135°, or from about 0° to about 90°. Pressing the injector 42 again then moves the key along step 35 “B” to position “C”, and the pusher 40 a corresponding length The conduit may be made from any biocompatible material to dispense another implant. Multiple implants may be deliv including, but not limited to, stainless Steel and any of its ered in this fashion, with the number of implants delivered alloys; titanium alloys, e.g., nickel-titanium alloys; polymers, depending on the number of steps in the stepped slot. e.g., polyethylene and copolymers thereof, polyethylene Although the various implant delivery devices described terephthalate or copolymers thereof, nylon, silicone, polyure 40 above deploy solid implants, this invention also contemplates thanes, fluoropolymers, poly(vinylchloride), and combina the use of the devices to deliver various semi-solid implants tions thereof, depending on the amount of flexibility or stiff and gels into the sinus. A force applied to a predetermined ness desired. The pusher may be made from similar materials. amount of a semi-solid implant or gel composition in the Usually, the device will be preloaded with a single implant conduit, e.g., by contact with a pusher or pressurized gas, within the lumen of the conduit, but more than one implant 45 may be preloaded if desired. Once access through a sinus could be used to deliver the implant or gel into the sinus. ostium has been obtained with the conduit, the pusher slid Applications ably engages the implant and is advanced until the implant The implants may be used to treat sinusitis affecting one or exits the catheter into the sinus. An endoscope may also be more of the maxillary sinus, the frontal sinus, the ethmoidal used while positioning the conduit to aid with visualization of 50 sinus, and the sphenoidal sinus. the ostium. Furthermore, the biodegradable implants may be used to In certain cases, e.g., when ostia are closed or difficult to treat acute or chronic sinusitis arising from predisposing ana access, implant placement into one or more sinuses may be tomical conditions, chronic allergic processes, or conditions completed through the sinus wall using a sharp-tipped con related to infection by various pathogens (e.g., bacteria, duit, e.g., a needle, trocar, or angiocatheter, with or without 55 fungi, and viruses). visualization using computer image-guided technology or Examples of bacteria that may cause sinusitis include endoscopy. Once the appropriate access point for the sinus Alpha-hemolytic streptococci, Beta-hemolytic Streptococci, has been determined, force is applied to the sharp-tipped Branhamella catarrhalis, Diptheroids, Haemophilis influen conduit so that it punctures the sinus wall. Advancement of a Zae, Moraxella species, Pseudomonas aeroginosa, pusher through the conduit lumen then deposits an implant 60 Pseudomonas maltophilia, Serratia marcescens, Staphyllo into the sinus. coccus aureus, and Streptococcus pneumoniae. FIGS. 1A-1B show examples of single implant delivery Examples of fungi that may cause sinusitis include devices. The devices include an implant 10, a conduit 12 Aspergillosis, Candida, Cryptococcus, Coccidioides, Histo having a side wall 14, a lumen 16, a distal portion 18, an plasma, and Mucor species. opening 20 in the distal portion 18, a tip 22, and a pusher 24. 65 The biodegradable implants may also be used to reduce In FIG. 1A, the conduit 12 includes a ramp 26 and an opening inflammation resulting from a sinus procedure, typically, a 20 positioned in the side wall 14. If delivering a solid implant, sinus drainage procedure. Examples of sinus drainage proce US 7,544,192 B2 10 dures include, but are not limited to, widening/enlargement of wherein the one or more biodegradable implants comprise a narrowed ostium, antral puncture and washout, and intra atherapeutic amount of an active agent for the treatment nasal antrostomy. The implants may be delivered into a sinus of sinusitis. using one of the methods previously described, usually after 2. The method of claim 1 wherein creating access com the procedure is completed, but they can also be delivered into 5 prises advancing the conduit through a paranasal sinus a sinus before the procedure or during the procedure. ostium. If enlarging an ostium, the affected sinus will generally be 3. The method of claim 1 wherein creating access com accessed through that enlarged ostium. The biodegradable prises advancing the conduit through a paranasal sinus wall. implant(s) may then be deployed into the sinus via the 4. The method of claim 1 wherein delivering the one or enlarged ostium. With respect to antral puncture and drainage 10 more biodegradable implants comprises delivering the one or or intranasal antrostomy, the affected sinus usually will be more biodegradable implants with a pusher. accessed at the antral puncture site or through the antrostomy. 5. The method of claim 1 wherein delivering the one or The biodegradable implant(s) will also usually be deployed more biodegradable implants comprises contacting the one or into the sinus through the antral puncture site orantrostomy. more biodegradable implants with a pressurized gas. However, if desired, the biodegradable implant(s) may be 15 6. The method of claim 1 wherein the distal portion of the delivered through a natural ostium despite antral puncture or conduit is angulated. antrostomy being perfomed. 7. The method of claim 1 wherein the conduit is sharp Method of Making the Implants tipped. The method of preparing the implants of this invention will 8. The method of claim 1 wherein the distal opening is generally depend on the particular therapeutic agent or matrix located in the side wall of the conduit. polymer used, form of the implant, and the release kinetics 9. The method of claim 1 wherein the distal opening is desired, but may be made by any one of the numerous meth located at the tip of the conduit. ods known in the art. For example, the implants may be made 10. The method of claim 1 wherein the biodegradable by Such processes as compression, extrusion, molding, Sol implant is a biodegradable polymeric implant. vent evaporation, or solvent extraction. 25 11. A method for delivering a biodegradable implant into a All publications, patents, and patent applications cited paranasal sinus cavity comprising: herein are hereby incorporated by reference in their entirety a) loading one or more biodegradable implants into a con for all purposes to the same extent as if each individual duit having a lumen, a distal portion, a side wall, a tip, publication, patent, or patent application were specifically and an opening in the distal portion; and individually indicated to be so incorporated by reference. 30 b) creating access to the paranasal sinus cavity with the Although the foregoing invention has been described in some loaded conduit; and detail by way of illustration and example for purposes of c) delivering the one or more biodegradable implants clarity of understanding, it will be readily apparent to those of through the opening in the distal portion of the conduit ordinary skill in the art in light of the teachings of this inven into the paranasal sinus cavity, tion that certain changes and modifications may be made 35 wherein the one or more biodegradable implants comprise thereto without departing from the spirit and scope of the atherapeutic amount of an active agent for the reduction appended claims. of inflammation. The invention claimed is: 12. The method of claim 11 wherein creating access com 1. A method for delivering a biodegradable implant into a prises advancing the conduit through a paranasal sinus paranasal sinus cavity comprising: 40 ostium. a) loading one or more biodegradable implants into a con 13. The method of claim 11 wherein creating access com duit having a lumen, a distal portion, a side wall, a tip, prises advancing the conduit through a sinus wall. and an opening in the distal portion; 14. The method of claim 11 wherein the biodegradable b) creating access to the paranasal sinus cavity with the implant is a biodegradable polymeric implant. loaded conduit; and 45 15. The implant of claim 11 wherein the active agent com c) delivering the one or more biodegradable implants prises mometasone furoate. through the opening in the distal portion of the conduit into the paranasal sinus cavity, k k k k k